The present invention relates to new melanocortin receptor ligands. These ligands are cyclic peptide analogs that preferably exhibit selectivity for the MC-4 and/or the MC-3 receptors relative to the other melanocortin receptors (in particular the MC-1 receptor).
Melanocortin peptides (melanocortins) are natural peptide hormones in animals and man that bind to and stimulate MC-receptors. Examples of melanocortins are xcex1-MSH (melanocyte stimulating hormone), xcex2-MSH, xcex3-MSH, ACTH (adrenocorticotropic hormone) and their peptide fragments. MSH is mainly known for its ability to regulate peripheral pigmentation (Eberle 1988), whereas ACTH is known to induce steroidoneogenesis (Simpson and Waterman, 1988). The melanocortin peptides also mediate a number of other physiological effects. They are reported to affect motivation, learning, memory, behavior, inflammation, body temperature, pain perception, blood pressure, heart rate, vascular tone, natriuresis, brain blood flow, nerve growth and repair, placental development, aldosterone synthesis and release, thyroxin release, spermatogenesis, ovarian weight, prolactin and FSH secretion, uterine bleeding in women, sebum and pheromone secretion, sexual activity, penile erection, blood glucose levels, intrauterine fetal growth, food motivated behavior, as well as other events related to parturition.
ACTH and the various MSH peptides share the tetrapeptide core His-Phe-Arg-Trp. All of the peptides are derived from the proteolytic processing of the pro-peptide pre-opiomelanocortin (POMC). In the past several years, five distinct melanocortin receptor subtypes have been identified. These MC receptors belong to the class of 7 transmembrane domain G-protein coupled receptors. The five MC receptors, termed MC-1, MC-2, MC-3, MC-4 and MC-5, all couple in a stimulatory fashion to cAMP. Of these, the MC-2 receptor is the ACTH receptor, whereas the others constitute subtypes of MSH receptors. The MC-1receptor is present on melanocytes and melanoma. The MC-2 receptor is present predominantly in the adrenal gland. The mRNA for the MC-3 receptor has been found in the brain, as well as in placental and gut tissues (Gantz et al. 1993a, Desamaud et al. 1994, Roselli Rehfuss et al. 1993). The MC-4 receptor has been found primarily in the brain (Gantz et al. 1993b; Mountjoy et al 1994). The MC-5 receptor is expressed in the brain, as well as in several peripheral tissues (Chhajlani et al 1993; Gantz et al 1994; Griffon et al 1994; Labbu et al. 1994; Barrett et al. 1994; Fathi et al.1995). More recent data from humans indicate that all of the cloned MC-receptors have a wider tissue distribution (Chhajlani, 1996) than originally thought.
As discussed above, the members of the melanocortin receptor family can be differentiated on the basis of their tissue distribution. Both the MC-4 and MC-3 receptors have been localized to the hypothalamus, a region of the brain believed to be involved in the modulation of feeding behavior. Compounds showing selectivity for the MC-4/MC-3 receptors have been shown to alter food intake following intracerebroventricular and peripheral injection in rodents. Specifically, agonists have been shown to reduce feeding, while antagonists have been shown to increase feeding. See, Fan, W. et al., xe2x80x9cRole of Melanocortinergic Neurons in Feeding and the Agouti Obesity Syndromexe2x80x9d, Nature, 385(6612), pp. 165-8 (Jan. 9, 1997).
The role of the MC-4 receptor subtype has been more clearly defined in the control of eating and body weight regulation in mammals. See, e.g., Huszer, D. et al., xe2x80x9cTargeted Disruption of the Melanocortin-4 Receptor Results in Obesity in Micexe2x80x9d, Cell, pp. 131-141 (1997); Klebig, M. L. et al., xe2x80x9cEctopic Expression of the Agouti Gene in Transgenic Mice Causes Obesity, Features of Type II Diabetes, and Yellow Furxe2x80x9d, Proc. Natl Acad Sci., Vol. 92, pp. 4728-32 (1995); Karbon, W. et al., xe2x80x9cExpression and Function of Argt, a Novel Gene Related to Agoutixe2x80x9d, Abstract from the Nineteenth Annual Winter Neuropeptide Conference (1998); Fan, W. et al., xe2x80x9cRole of Melanocortinergic Neurons in Feeding and the Agouti Obesity Syndromexe2x80x9d, Nature, Vol. 385, pp. 165-168 (1997); Seely, R. J., xe2x80x9cMelanocortin Receptors in Leptin Effectsxe2x80x9d, Nature, Vol. 390, p. 349 (1997); Comuzzie, A. G., xe2x80x9cA Major Quantitative Trait Locus Determining Serum Leptin Levels and Fat Mass is Located on Human Chromosome 2xe2x80x9d, Nat. Gen., Vol. 15, pp. 273-276 (1997); Chagnon, Y. C. et al., xe2x80x9cLinkage and Association Studies Between the Melanocortin Receptors 4 and 5 Genes and Obesity-Related Phenotypes in the Quebec Family Studyxe2x80x9d, Mol. Med., Vol 3(10), pp. 663-673 (1997); Lee, F. and Huszar, D, xe2x80x9cScreening Methods for Compounds Useful in the Regulation of Body Weightxe2x80x9d, World Patent Publication WO 97/47316 (1997); and Shutter, J. R. et al., xe2x80x9cHypothalamic Expression of ART, a Novel Gene Related to Agouti, is Up-Regulated in Obese and Diabetic Mutant Micexe2x80x9d, Gen. and Dev. Vol. 11, pp. 593-602 (1997). Stimulation of the MC-4 receptor by its endogenous ligand, CCMSH, produces a satiety signal and may be the downstream mediator of the leptin satiety signal. It is believed that by providing potent MC-4 receptor agonists, appetite may be suppressed and weight loss benefits may be achieved.
Applicants have discovered a class of compounds that surprisingly have high affinity for the MC-4 and/or the MC-3 receptor subtypes, and that are typically selective for these MC receptors relative to the other melanocortin receptor subtypes, particularly the MC-1 subtype. It is therefore an object of this invention to provide chemical compounds that activate or antagonize the MC-4 and/or the MC-3 receptor subtypes. It is a further object of the invention to provide means for administration of said compounds to animals or man. Still other objects of the invention will be evident from the following disclosure of the invention.
Applicants have discovered certain structural requirements for a class of cyclic peptide analogs that are ligands for receptors of the MC-4 and/or the MC-3 subtype. The structural requirements constitute an optimal ring size of the peptide analog cycle at the proper location in the analog, as is described below. Thus, the present invention relates to a cyclic peptide analog having a structure according to Formula (I): 
wherein
(A) each of m, n, and q is independently selected from 0 to about 4 and p is from 0 to about 5;
(B) X, which represents the four substituents on the phenyl ring other than E and (CH2)m, is independently selected from hydrogen; halo; OR8; xe2x80x94SR8; xe2x80x94NR8R8xe2x80x2; xe2x80x94N(R8)SO2R8xe2x80x3; xe2x80x94SO2R8xe2x80x3; xe2x80x94SO2xe2x80x94NR8R8xe2x80x2; alkyl; alkene; alkyne; cyano; nitro; CF3; aryl; heteroaryl; cycloalkyl; heterocycloalkyl; and xe2x80x94(CH2)rxe2x80x94PO2HR14 where r is 0 to about 10 and R14 is selected from xe2x80x94OH, hydrogen and alkyl; where each R8 and R8xe2x80x2 is independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl and R8xe2x80x3 is selected from hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; or two X moieties can together form a fused ring with the depicted phenyl ring;
(C) E is selected from hydrogen; halo; xe2x80x94OR13; xe2x80x94SR13; xe2x80x94NR13R13xe2x80x2; xe2x80x94N(R13)SO2R13xe2x80x3; xe2x80x94SO2R13xe2x80x3; xe2x80x94SO2xe2x80x94NR13R13xe2x80x2; xe2x80x94(CH2)rxe2x80x94PO2HR15 where r is 0 to about 10 and R5 is selected from xe2x80x94OH, hydrogen and alkyl; alkyl; alkene; alkyne; cyano; nitro; CF3; aryl; heteroaryl; cycloalkyl; and heterocycloalkyl; provided that when each X is hydrogen, E is not hydrogen; where each R13 and R13xe2x80x2 is independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl and R13xe2x80x3 is selected from hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
(D) Z is one or more substituents independently selected from hydrogen, hydroxy, halo, thiol, xe2x80x94OR9, xe2x80x94SR9, xe2x80x94NR9R9xe2x80x2, alkyl, acyl, alkene, alkyne, cyano, nitro, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; where each R9 and R9xe2x80x2 is independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; or some Z moieties can form a fused ring with the depicted phenyl ring;
(E) D is selected from xe2x80x94N(R2)C(xe2x95x90NR3)NR4R5, an optionally substituted imidazole ring, and xe2x80x94NR4R5, wherein
(1) R2 and R3 are independently selected from hydrogen, alkyl, and alkyne; or R2 and r3, together with the atoms to which they are bondded, joint to from a heterocycloalkyl or a heteroaryl; or R2 and R4, together with the atoms to which they are bonded, joint to form a heteropcycloalkyl or a heteroaryl; or R3 and R4, together with the atoms to which they are bonded, joint to form a heterocycloalkyl or a heteroaryl; and
(2) R4 and R5 are independently selected from hydrogen, alkyl, alkene, and alkyne; or R4 and R5, together with the atoms to which they are bonded, join to form a heterocycloalkyl or a heteroaryl;
(F) each R1 and R1xe2x80x2 is independently selected from hydrogen, alkyl, aryl and heteroaryl; or two R1 moieties, together with the carbon atoms to which they are bonded, join to form a cycloalkyl or aryl ring; or an R1 and R2 (if present), together with the atoms to which they are bonded, join to form a heterocycloalkyl or a heteroaryl; or an R1 and R3 (if present), together with the atoms to which they are bonded, join to form a heterocycloalkyl or a heteroaryl; or an R1 and R4 (if present), together with the atoms to which they are bonded, join to form a heterocycloalkyl or a heteroaryl;
(G) G is selected from an optionally substituted bicyclic aryl ring and an optionally substituted bicyclic heteroaryl ring;
(H) each R11 is independently selected from hydrogen, alkyl, alkene, alkyne, aryl, heteroaryl, and cycloalkyl; and each R is independently selected from hydrogen, alkyl, alkene, alkyne, aryl, heteroaryl, and cycloalkyl; or an R11 moiety can join with an adjacent R moiety to form a ring;
(I) W is selected from covalent bond, xe2x80x94CH2xe2x80x94 and xe2x80x94C(xe2x95x90O)xe2x80x94;
(J) Mxe2x80x2 is selected from covalent bond, xe2x80x94Nxe2x80x94 and xe2x80x94CHxe2x80x94; and
(K) B is an optionally substituted bridge moiety that links Mxe2x80x2 and W to form a ring and comprises either a covalent bond or an ionic bond, wherein when the bridge moiety comprises an ionic bond it is unsubstituted or is substituted with not more than 3 amino acid residues;
provided that when the compound comprises less than 25 ring atoms, then the phenyl ring substituted with Z is of the D-configuration (xe2x80x9cD-Phexe2x80x9d or xe2x80x9cfxe2x80x9d) and further provided that when B comprises two or more Cys residues that form one or more disulfide bonds, said disulfide bond(s) is not necessary for the existence of the cyclic peptide analog of Formula (I).
The invention also relates to pharmaceutical compositions comprising the above compounds, and to methods of treating disorders mediated by the MC-3 or MC-4 receptor by administering these compounds.